There are high unmet medical needs in the limited biologic therapeutics for 1.0% of adults with rheumatoid arthritis [RA] associated with staggering $39.2 billion annual US health care and societal costs. These are due to inadequate efficacy;patient's inconvenience, prohibitive costs, poor adherence and treatment discontinuations;manufacturing risks and safety issues (infections &malignancies) that have prompted critical regulatory actions. Oral RA therapies are warranted due to their inherent lesser safety risks, lower costs and flexible drug delivery formulations for utility in various autoimmune diseases [AD]. Persistent safety findings of oral kinase inhibitors in development for RA continue to justify a target-selective approach that limits disease progression without the unwarranted toxicities of non-specific generalized over-immunosuppression. Selective inhibition of macrophage migration inhibitory factor [MIF] has been target validated demonstrating unprecedented superior safety and efficacy in preclinical RA and several AD models. Innovimmune's [INV] proprietary new chemical entities of INV-88 lead scaffolds were discovered in silico using fragment-based coupled with structure-based drug design and are the first oral MIF inhibitors that target critical MIF pharmacophores taking advantage of emerging scientific advances in contrast to earlier oral MIF inhibitors. An INV team of expert drug developers with an industry track record of successfully advancing >35 RA and AD therapeutics will lead the 24-month SBIR Phase I INV-88 lead optimization. The Phase I goal of clinical lead candidate selection will be achieved by accomplishing two specific aims of (1) lead candidate identification and characterization and (2) demonstration of anti-inflammatory proof of concept. The lead candidate could advance to a 36-month SBIR Phase II Preclinical/IND-enabling research stage with a goal to complete the ICH-M3(R2) requirements that will enable an FDA IND filing for RA in 2016. The SBIR Phase II milestone completion will enable a Phase 1 First in Human clinical study start in 2016, an increasing company asset valuation through strong intellectual property position and increasing estate, and potential extension of clinical development in the other high-growth MIF-target validated AD diseases. This accomplishment would place INV in a position of strength as it seeks an outlicensing, M&A or codevelopment agreement with external stakeholders. INV will seek potential industry development partners and investors as early as in SBIR Phase I to supplement the Phase I and II SBIR funding, and thus securing a partner early-on to lead further clinical development, NDA approval and commercialization. A future FDA approval for INV-88 as the first orally available target-selective cytokine inhibitor with a potential for better potency and efficacy, superior safety profile, wider therapeutic index, and cost-effective oral immunotherapy convenient for RA and AD patients would fulfill all critical unmet medical needs by contributing to overall patient mortality and quality of life improvements, and reduced public health care and societal costs. PUBLIC HEALTH RELEVANCE: The project's goal is to develop the first target-selective cytokine oral therapy that is safe and efficacious for rheumatoid arthritis [RA] and other autoimmune diseases [AD] with a small molecule macrophage migration inhibitory factor [MIF] inhibitor. The primary objective of the SBIR Phase I proposal is the lead optimization research of Innovimmune's proprietary oral MIF inhibitors. An FDA approval of an oral MIF inhibitor with a potential for better potency and efficacy, superior safety profile, wider therapeutic index, and cost-effective oral immunotherapy convenient for RA and AD patients would fulfill all critical unmet medical needs by contributing to overall patient mortality and quality of life improvements, and reduced public health care and societal costs.